Pål Smith

The Effect of Warfarin on Mortality and Reinfarction after Myocardial Infarction

BACKGROUND AND METHODS The use of oral anticoagulation in the long-term treatment of survivors of acute myocardial infarction has been highly controversial. We therefore randomly assigned 1214 patients who had recovered from acute myocardial infarction (mean interval from the onset of symptoms to randomization, 27 days) to treatment with warfarin (607 patients) or placebo (607 patients) for an average of 37 months (range, 24 to 63). RESULTS At the end of the treatment period, there had been 123 deaths in the placebo group and 94 in the warfarin group--a reduction in risk of 24 percent (95 percent confidence interval, 4 to 44 percent; P = 0.027). A total of 124 patients in the placebo group had reinfarctions, as compared with 82 in the warfarin group--a reduction of 34 percent (95 percent confidence interval, 19 to 54 percent; P = 0.0007). Furthermore, we observed a reduction of 55 percent (95 percent confidence interval, 30 to 77 percent) in the number of total cerebrovascular accidents in the warfarin group as compared with the placebo group (44 vs. 20; P = 0.0015). Serious bleeding was noted in 0.6 percent of the warfarin-treated patients per year. CONCLUSIONS Long-term therapy with warfarin has an important beneficial effect after myocardial infarction and can be recommended in the treatment of patients who survive the acute phase.

Statin use is associated with reduced mortality in COPD

Patients with chronic obstructive pulmonary disease (COPD) have an increased risk of ischaemic heart disease (IHD). Statins reduce mortality and morbidity in IHD. It has been hypothesised that statin treatment is associated with reduced long-term mortality in patients with COPD. Using a retrospective cohort design, 854 consecutive patients (mean age 70.8 yrs; 51.5% female) with a diagnosis of COPD exacerbation were included in the study at discharge from a Norwegian teaching hospital. Median follow-up was 1.9 yrs, during which 333 patients died. The crude mortality rate per 1,000 person-yrs was 110 in patients treated with statins, and 191 in patients not treated with statins. After adjustment for sex, age, smoking, pulmonary function and comorbidities, the hazard ratio (HR) for statin users versus statin nonusers was 0.57 (95% confidence interval 0.38–0.87). When subdividing statin users and statin nonusers into groups according to concomitant treatment with inhaled corticosteroids (ICS) the following HRs were found: 0.75 (0.58–0.98) for ICS only; 0.69 (0.36–1.3) for statins only; and 0.39 (0.22–0.67) for the combined treatment with statin and ICS compared with no such treatment. Treatment with statins was associated with improved survival after chronic obstructive pulmonary disease exacerbation, while inhaled corticosteroids appeared to increase the survival benefit associated with statin use.

The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study

Background— During follow-up of between 1 and 3 years in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, 2 doses of dabigatran etexilate were shown to be effective and safe for the prevention of stroke or systemic embolism in patients with atrial fibrillation. There is a need for longer-term follow-up of patients on dabigatran and for further data comparing the 2 dabigatran doses. Methods and Results— Patients randomly assigned to dabigatran in RE-LY were eligible for the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit. Enrolled patients continued to receive the double-blind dabigatran dose received in RE-LY, for up to 28 months of follow up after RE-LY (median follow-up, 2.3 years). There were 5851 patients enrolled, representing 48% of patients originally randomly assigned to receive dabigatran in RE-LY and 86% of RELY-ABLE–eligible patients. Rates of stroke or systemic embolism were 1.46% and 1.60%/y on dabigatran 150 and 110 mg twice daily, respectively (hazard ratio, 0.91; 95% confidence interval, 0.69–1.20). Rates of major hemorrhage were 3.74% and 2.99%/y on dabigatran 150 and 110 mg (hazard ratio, 1.26; 95% confidence interval, 1.04–1.53). Rates of death were 3.02% and 3.10%/y (hazard ratio, 0.97; 95% confidence interval, 0.80–1.19). Rates of hemorrhagic stroke were 0.13% and 0.14%/y. Conclusions— During 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00808067.

Antiphospholipid antibodies after myocardial infarction and their relation to mortality, reinfarction, and non-haemorrhagic stroke

Antiphospholipid antibodies have been suggested as markers for a high risk of recurrent cardiovascular events in young survivors of an acute myocardial infarction. However, there are few data to confirm or refute this hypothesis. In a cohort study, we have measured anticephalin (aCEPHA) and anticardiolipin (aCL) antibodies in a group of patients surviving an acute infarct. Of 597 patients studied, 13.2% were IgG or IgM aCEPHA positive compared with 4.4% of a reference population (n = 158; p = 0.002). In a multivariate analysis, adjusted for major cardiovascular risk factors, neither aCEPHA (IgG or IgM) nor a CL (IgG or IgM) was an independent risk factor for mortality, reinfarction, or non-haemorrhagic stroke. Although an increased proportion of survivors of a myocardial infarction have antiphospholipid antibodies, the presence of such antibodies is not a risk factor for subsequent coronary or cerebrovascular thrombosis.

Invasive versus conservative strategy in patients aged 80 years or older with non-ST-elevation myocardial infarction or unstable angina pectoris (After Eighty study): an open-label randomised controlled trial

BACKGROUND Non-ST-elevation myocardial infarction (NSTEMI) and unstable angina pectoris are frequent causes of hospital admission in the elderly. However, clinical trials targeting this population are scarce, and these patients are less likely to receive treatment according to guidelines. We aimed to investigate whether this population would benefit from an early invasive strategy versus a conservative strategy. METHODS In this open-label randomised controlled multicentre trial, patients aged 80 years or older with NSTEMI or unstable angina admitted to 16 hospitals in the South-East Health Region of Norway were randomly assigned to an invasive strategy (including early coronary angiography with immediate assessment for percutaneous coronary intervention, coronary artery bypass graft, and optimum medical treatment) or to a conservative strategy (optimum medical treatment alone). A permuted block randomisation was generated by the Centre for Biostatistics and Epidemiology with stratification on the inclusion hospitals in opaque concealed envelopes, and sealed envelopes with consecutive inclusion numbers were made. The primary outcome was a composite of myocardial infarction, need for urgent revascularisation, stroke, and death and was assessed between Dec 10, 2010, and Nov 18, 2014. An intention-to-treat analysis was used. This study is registered with ClinicalTrials.gov, number NCT01255540. FINDINGS During a median follow-up of 1·53 years of participants recruited between Dec 10, 2010, and Feb 21, 2014, the primary outcome occurred in 93 (40·6%) of 229 patients assigned to the invasive group and 140 (61·4%) of 228 patients assigned to the conservative group (hazard ratio [HR] 0·53 [95% CI 0·41-0·69], p=0·0001). Five patients dropped out of the invasive group and one from the conservative group. HRs for the four components of the primary composite endpoint were 0·52 (0·35-0·76; p=0·0010) for myocardial infarction, 0·19 (0·07-0·52; p=0·0010) for the need for urgent revascularisation, 0·60 (0·25-1·46; p=0·2650) for stroke, and 0·89 (0·62-1·28; p=0·5340) for death from any cause. The invasive group had four (1·7%) major and 23 (10·0%) minor bleeding complications whereas the conservative group had four (1·8%) major and 16 (7·0%) minor bleeding complications. INTERPRETATION In patients aged 80 years or more with NSTEMI or unstable angina, an invasive strategy is superior to a conservative strategy in the reduction of composite events. Efficacy of the invasive strategy was diluted with increasing age (after adjustment for creatinine and effect modification). The two strategies did not differ in terms of bleeding complications. FUNDING Norwegian Health Association (ExtraStiftelsen) and Inger and John Fredriksen Heart Foundation.

Troponin T elevation and long-term mortality after chronic obstructive pulmonary disease exacerbation

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular disease, exacerbations of which increase strain on the heart. The prognostic value of elevated circulating levels of cardiac Troponins seen during COPD exacerbations has been investigated. From the Akershus hospital database, 897 patients discharged after treatment for COPD exacerbation in the period 2000–2003 were identified and followed-up until June 30, 2005. Median observation time was 1.9 yrs. In 396 patients, measurements of cardiac-specific troponin T (cTnT) were available. Levels of cTnT ≥0.04 μg·L−1 were considered elevated. Clinical data were retrieved from patient records and date of death was obtained from the Norwegian National Registry. In order to balance the nonrandomised nature of available cTnT measurements, an exposure propensity score (EPS) for cTnT sampling was calculated and used in regression analyses. After adjusting for EPS in Cox regression analyses, elevated cTnT was significantly associated with increased all-cause mortality in the observation period, with a hazard ratio of 1.64 (95% confidence interval 1.15–2.34). In conclusion, chronic obstructive pulmonary disease patients with elevated cardiac-specific Troponin T during exacerbation are at increased risk of death after discharge.

Atrial Fibrillation and Antithrombotic Therapy in a 75-Year-Old Population

Aims: To find the true prevalence of diagnosed and undiagnosed atrial fibrillation (AF) in a population aged 75 years in 2 municipalities in Norway, and to study the use of antithrombotic therapy in this group. Methods: All 1,117 citizens in Asker and Baerum municipalities in eastern Norway born in 1930 were invited to participate in a prevalence study of AF. Nine hundred and sixteen subjects (82%) were examined by electrocardiogram, and blood pressure and pulse rate were measured. Comorbidity and current medication were recorded. Results: AF was present in 92 subjects (10%; 95% CI 8.2–12.1%), including 33 with ECG-documented, paroxysmal AF. In addition, 8 subjects had a history of a single, transient episode of AF. AF was previously undiagnosed in 10 out of 916 (1.1%). In 77 of 82 patients with previously diagnosed AF (93.9%), antithrombotic therapy was compliant with international guidelines. Conclusion: Ten percent (95% CI 8.2–12.2%) in this 75-year-old population had AF. Compliance with international guidelines regarding antithrombotic therapy was high. Previously undiagnosed AF was found in only 10 out of 916 (1.1%).

Influence of highly concentrated n-3 fatty acids on serum lipids and hemostatic variables in survivors of myocardial infarction receiving either oral anticoagulants or matching placebo

Forty patients with previous myocardial infarction were given 4 capsules with 1 g concentrated fish oil preparation daily for 4 weeks. No special diet was applied. The supplementation was equivalent to 3.4 grams of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) daily. Twenty-two of the 40 subjects received concomitant treatment with long-term oral anticoagulants (OAC). The fatty acid composition of serum after the supplementation period showed a significant increase in the proportion of EPA and DHA, while arachidonic acid (AA) remained essentially constant. This resulted in a rise of the EPA/AA ratio from 0.59 to 1.49 (p less than 0.001), confirming satisfying absorption of the concentrate. Blood lipids showed an overall decrease of triglycerides (TG) by 25% (p = 0.02), while total cholesterol rose by 5% (p = 0.03) and HDL-cholesterol was unaffected. Blood glucose and the TG associated factors plasminogen activator inhibitor and factor VII-phospholipid complex revealed trends towards reduction. Ivy bleeding time showed a significant prolongation, the median increasing from 240 to 270 seconds. A significant increase of fibrinogen was seen, as was a decrease of clotting time in the combined prothrombin test in patients receiving concomitant OAC. Thus, given for 4 weeks, the investigated concentrate of n-3 fatty acids exerts not merely beneficial effects as far as the risk profile for atherosclerotic disease is concerned. The results also point towards interactions with OAC that may be of clinical relevance.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Warfarin, Aspirin and the Two Combined, on Mortality and Thromboembolic Morbidity after Myocardial Infarction: The WARIS-II (Warfarin-Aspirin Reinfarction Study) Design

The efficacy and safety of warfarin, aspirin, and the two combined are compared in a long-term, randomized, open, multicentre study involving 3606 patients after acute myocardial infarction (1202 in each treatment group). In this trial three groups receive either warfarin, aimed at a therapeutic level of the International Normalized Ratio (INR) 2.8-4.2, or 160 mg aspirin daily, or 75 mg aspirin daily combined with warfarin with INR 2.0-2.5. A placebo group is not included. Patients are screened before randomization and are given major examinations at 4 weeks and at the end of the study. In addition, all patients are given a questionnaire every 6 months. Composite endpoints include death, non-fatal reinfarction and cerebral stroke. All analyses are conducted on the intention-to-treat principle and on on-efficacy basis. The analyses control for recruiting centre, use of beta blockade, use of thrombolytic therapy and use of angiotensin converting enzyme (ACE) inhibitors.The efficacy and safety of warfarin, aspirin, and the two combined are compared in a long-term, randomized, open, multicentre study involving 3606 patients after acute myocardial infarction (1202 in each treatment group). In this trial three groups receive either warfarin, aimed at a therapeutic level of the International Normalized Ratio (INR) 2.8-4.2, or 160 mg aspirin daily, or 75 mg aspirin daily combined with warfarin with INR 2.0-2.5. A placebo group is not included. Patients are screened before randomization and are given major examinations at 4 weeks and at the end of the study. In addition, all patients are given a questionnaire every 6 months. Composite endpoints include death, non-fatal reinfarction and cerebral stroke. All analyses are conducted on the intention-to-treat principle and on on-efficacy basis. The analyses control for recruiting centre, use of beta blockade, use of thrombolytic therapy and use of angiotensin converting enzyme (ACE) inhibitors.

Determinants of cardiac troponin T elevation in COPD exacerbation – a cross-sectional study

BackgroundCardiac Troponin T (cTnT) elevation during exacerbations of chronic obstructive pulmonary disease (COPD) is associated with increased mortality the first year after hospital discharge. The factors associated with cTnT elevation in COPD are not known.MethodsFrom our hospitals database, all patients admitted with COPD exacerbation in 2000–03 were identified. 441 had measurement of cTnT performed. Levels of cTnT ≥ 0.04 μg/l were considered elevated. Clinical and historical data were retrieved from patient records, hospital and laboratory databases. Odds ratios for cTnT elevation were calculated using logistic regression.Results120 patients (27%) had elevated cTnT levels. The covariates independently associated with elevated cTnT were increasing neutrophil count, creatinine concentration, heart rate and Cardiac Infarction Injury Score (CIIS), and decreasing hemoglobin concentration. The adjusted odds ratios (95% confidence intervals in parentheses) for cTnT elevation were 1.52 (1.20–1.94) for a 5 × 106/ml increase in neutrophils, 1.21 (1.12–1.32) for a 10 μmol/l increase in creatinine, 0.80 (0.69–0.92) for a 1 mg/dl increase in hemoglobin, 1.24 (1.09–1.42) for a 10 beats/minute increase in heart rate and 1.44 (1.15–1.82) for a 10 point increase in CIIS.ConclusionMultiple factors are associated with cTnT elevation, probably reflecting the wide panorama of comorbid conditions typically seen in COPD. The positive association between neutrophils and cTnT elevation is compatible with the concept that an exaggerated inflammatory response in COPD exacerbation may predispose for myocardial injury.